Signal Transduction Mediated by the T‐Cell Antigen Receptor

Samelson, Lawrence E.; Donovan, Jerald A.; Isakov, Noah; Ota, Yasuo; Wange, Ronald L.

doi:10.1111/j.1749-6632.1995.tb26659.x

Cited by 129 publications

(181 citation statements)

References 73 publications

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“…We thus studied whether defective MAPK activation could be attributed to an inhibition on proximal TCR activation by Deltex. TCR engagement is immediately followed by recruitment and tyrosine phosphorylation of the adaptor protein LAT; LAT is pivotal for activation of AP-1 and ERK (40). Figure 4D illustrates that anti-CD3 stimulation of T cells led to extensive LAT phosphorylation, identical in Deltex1-DO11.10 and YFP-DO11.10 cells, suggesting that Deltex1 does not affect early T-cell activation at the stage of LAT phosphorylation.…”

Section: Physiological Role Of Deltex In T-cell Activationmentioning

confidence: 99%

Deltex Regulates T-Cell Activation by Targeted Degradation of Active MEKK1

Liu

Lai

2005

Molecular and Cellular Biology

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Section: Physiological Role Of Deltex In T-cell Activationmentioning

confidence: 99%

Deltex Regulates T-Cell Activation by Targeted Degradation of Active MEKK1

Liu

Lai

2005

Molecular and Cellular Biology

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“…T cells play a pivotal role in acquired immune reaction and have been implicated in mediating many aspects of autoimmune diseases [7]. Firstly, TCR cross-linking drives T cells from G0 to G1 transition and subsequent secretion of T cell growth factor IL-2 and expression of highaffinity receptor IL-2Rα chain (CD25); secondly, through autocrine/ paracrine proliferative loop, IL-2 induces clone expansion and maintains survival of activated T cells; thirdly, once there is successful clearance of the pathogen/autoantigen, the stimulus for cytokines production is lost and the majority of activated T cells enter apoptosis [8,9].…”

Section: Introductionmentioning

confidence: 99%

SM934, a water-soluble derivative of arteminisin, exerts immunosuppressive functions in vitro and in vivo

Hou

Wang

et al. 2009

International Immunopharmacology

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“…However, it remains to be determined precisely how TCR signaling is initiated and propagated intracellularly during thymic selection. The first step in initiating the TCR signaling cascade is thought to be the phosphorylation of tyrosine residues in immunoreceptor tyrosine-based activation motifs (ITAMs) of the CD3ζ chain by the Src family tyrosine kinase Lck (9)(10)(11). Phosphorylated ITAMs of the CD3ζ chain then recruit tyrosine kinase Zap70 to the TCR complexes, where it can be activated by autophosphorylation.…”

mentioning

confidence: 99%

Grb2 functions at the top of the T-cell antigen receptor–induced tyrosine kinase cascade to control thymic selection

Jang

Zhang

Chiang

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Grb2 is an adaptor molecule that mediates Ras-MAPK activation induced by various receptors. Here we show that conditional ablation of Grb2 in thymocytes severely impairs both thymic positive and negative selections. Strikingly, the mutation attenuates T-cell antigen receptor (TCR) proximal signaling, including tyrosine phosphorylation of multiple signaling proteins and Ca 2+ influx. The defective TCR signaling can be attributed to a marked impairment in Lck activation. Ectopic expression of a mutant Grb2 composed of the central SH2 and the C-terminal SH3 domains in Grb2 −/− thymocytes fully restores thymocyte development. Thus, Grb2 plays a pivotal role in both thymic positive and negative selection. It amplifies TCR signaling at the top end of the tyrosine phosphorylation cascade via a scaffolding function.T lymphopoiesis is a sequential developmental process regulated by multiple environmental signals. The final outcome is the generation of different lineages of T cells with a diverse antigen receptor repertoire (1-4). Diversification of the T-cell antigen receptor (TCR) is initially generated through successive rearrangements of the V-(D)-J genes in CD4 and CD8 doublenegative (DN) T precursors. Successful rearrangement of the TCR β gene allows DN T cells to express pre-TCR and to develop into CD4 and CD8 double-positive (DP) cells, at which stage the TCR repertoire is further shaped by thymic selection. Cells expressing a TCR with too strong or too weak an affinity/avidity for MHC-peptide complexes will die via apoptosis, the processes termed negative selection or neglect. In contrast, cells bearing a TCR with moderate avidity toward MHC-peptide complexes will survive the selection (positive selection) and become mature CD4 + or CD8 + single positive (SP) thymocytes (5-8).The importance of TCR signaling in thymic positive and negative selection has been demonstrated in a variety of experimental models. However, it remains to be determined precisely how TCR signaling is initiated and propagated intracellularly during thymic selection. The first step in initiating the TCR signaling cascade is thought to be the phosphorylation of tyrosine residues in immunoreceptor tyrosine-based activation motifs (ITAMs) of the CD3ζ chain by the Src family tyrosine kinase Lck (9-11). Phosphorylated ITAMs of the CD3ζ chain then recruit tyrosine kinase Zap70 to the TCR complexes, where it can be activated by autophosphorylation. Upon activation, Zap70 phosphorylates the membrane anchor protein linker for activation of T cells (LAT), which in turn assembles signaling complexes containing multisignaling molecules, including Grb2, SLP-76, Vav, Gads, PLCγ-1, and Itk. The coordination between these signaling components in the complexes determines multiple downstream cellular responses, including Ca 2+ mobilization, cytoskeleton reorganization, and activation of nuclear transcription factors, which eventually define various T-cell development programs (9, 12-14).Grb2 is a positive regulator of Ras signaling downstream of many growth fa...

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Signal Transduction Mediated by the T‐Cell Antigen Receptor

Cited by 129 publications

References 73 publications

Deltex Regulates T-Cell Activation by Targeted Degradation of Active MEKK1

Deltex Regulates T-Cell Activation by Targeted Degradation of Active MEKK1

SM934, a water-soluble derivative of arteminisin, exerts immunosuppressive functions in vitro and in vivo

Grb2 functions at the top of the T-cell antigen receptor–induced tyrosine kinase cascade to control thymic selection

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